西亚试剂：Nicotinamide N-methyltransferase knockdown protects against

Daniel Kraus, Qin Yang, Dong Kong, Alexander S. Banks, Lin Zhang, Joseph T. Rodgers,Eija Pirinen, Thomas C. Pulinilkunnil, Fengying Gong, Ya-chin Wang, Yana Cen, Anthony A. Sauve, John M. Asara, Odile D. Peroni, Brett P. Monia, Sanjay Bhanot, Leena Alhonen,Pere Puigserver & Barbara B. Kahn

In obesity and type 2 diabetes, Glut4 glucose transporter expressi0n is decreased selectively in adipocytes. Adipose-specific knockout or overexpressi0n of Glut4 alters systemic insulin sensitivity. Here we show, array analyses, that nicotinamide N-methyltransferase (Nnmt) is the most strongly reciprocally regulated gene when comparing gene expressi0n in white adipose tissue (WAT) from adipose-specific Glut4-knockout or adipose-specific Glut4-overexpressing mice with their respective controls. NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor of NAD+, an imp0rtant cofactor 1inking cellular redox states with energy me-tabolism. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation. Polyamine flux including synthesis, catabolism and excretion, is controlled by the rate-limiting enzymes ornithine decarboxylase (ODC) and spermidine–spermine N1-acetyltransferase (SSAT; encoded by Sat1) and by polyamine oxidase (PAO), and has a major role in energy me-tabolism. We report that NNMT expressi0n is increased in WAT and liver of obese and diabetic mice. Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure. NNMT inhibition increases adipose SAM and NAD+ levels and upregulates ODC and SSAT activity as well as expressi0n, owing to the effects of NNMT on histone H3 lysine 4 methylation in adipose tissue. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine me-tabolism. NNMT inhibition in adipocytes increases oxygen consumption in an ODC-, SSAT- and PAO-dependent manner. Thus, NNMT is a novel regulator of histone methylation, polyamine flux and NAD+-dependent SIRT1 signalling, and is a unique and attractive target for treating obesity and type 2 diabetes.

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